Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis

Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60–80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis

Formation of a galaxy with a central black hole in the Lemaitre-Tolman model

We construct two models of the formation a galaxy with a central black hole, starting from a small initial fluctuation at recombination. This is an application of previously developed methods to find a Lemaitre-Tolman model that evolves from a given initial density or velocity profile to a given final density profile. We show that the black hole itself could be either a collapsed object, or a non-vacuum generalisation of a full Schwarzschild-Kruskal-Szekeres wormhole. Particular attention is paid to the black hole's apparent and event horizons.Comment: REVTeX, 22 pages including 11 figures (25 figure files). Replacement has minor changes in response to the referee, and editorial corrections. To appear in PR

X-Ray Properties of Narrow-Line Seyfert 1 Galaxies with Very Small Broad-Line Widths

Narrow-line Seyfert\,1 galaxies (NLS1s) with very small broad-line widths (say, FWHM(\hb) \la 1200\,\kms) represent the extreme type of Seyfert\,1 galaxies that have small black hole masses (\mbh) and/or high Eddington ratios (\redd). Here we study the X-ray properties of a homogeneously and optically selected sample of 13 such objects, termed as very narrow line Seyfert\,1 galaxies (VNLS1s), using archival \xmm\ data. It is found that the Fe K$\alpha$ emission line is at most weak in these objects. A soft X-ray excess is ubiquitous, with the thermal temperatures falling within a strict range of 0.1--0.2\,keV. Our result highlights the puzzling independence of the thermal temperature by extending the relations to even smaller FWHM(\hb), i.e., smaller \mbh\ ($\sim 10^6$ \msun) and/or higher \redd. The excess emission can be modeled by a range of viable models, though the disk reflection and Comptonization models generally give somewhat better fits over the smeared absorption and the $p$-free models. At the Eddington ratios around unity and above, the X-ray spectral slopes in the 2--10\,keV band are systematically flatter than the Risaliti et al.'s predictions of the relationship with \redd\ suggested previously. Short timescale (1--2 hours) X-ray variability is common, which, together with the variability amplitude computed for some of the objects, are supportive of the scenario that NLS1s are indeed AGN with relatively small \mbh.Comment: 11 figures and 4 table. Accepted for publication in the Astrophysical Journa

Central Masses and Broad-Line Region Sizes of Active Galactic Nuclei. II. A Homogeneous Analysis of a Large Reverberation-Mapping Database

We present improved black hole masses for 35 active galactic nuclei (AGNs) based on a complete and consistent reanalysis of broad emission-line reverberation-mapping data. From objects with multiple line measurements, we find that the highest precision measure of the virial product is obtained by using the cross-correlation function centroid (as opposed to the cross-correlation function peak) for the time delay and the line dispersion (as opposed to full width half maximum) for the line width and by measuring the line width in the variable part of the spectrum. Accurate line-width measurement depends critically on avoiding contaminating features, in particular the narrow components of the emission lines. We find that the precision (or random component of the error) of reverberation-based black hole mass measurements is typically around 30%, comparable to the precision attained in measurement of black hole masses in quiescent galaxies by gas or stellar dynamical methods. Based on results presented in a companion paper by Onken et al., we provide a zero-point calibration for the reverberation-based black hole mass scale by using the relationship between black hole mass and host-galaxy bulge velocity dispersion. The scatter around this relationship implies that the typical systematic uncertainties in reverberation-based black hole masses are smaller than a factor of three. We present a preliminary version of a mass-luminosity relationship that is much better defined than any previous attempt. Scatter about the mass-luminosity relationship for these AGNs appears to be real and could be correlated with either Eddington ratio or object inclination.Comment: 61 pages, including 8 Tables and 16 Figures. Accepted for publication in The Astrophysical Journa

A dust-parallax distance of 19 megaparsecs to the supermassive black hole in NGC 4151

The active galaxy NGC 4151 has a crucial role as one of only two active galactic nuclei for which black hole mass measurements based on emission line reverberation mapping can be calibrated against other dynamical methods. Unfortunately, effective calibration requires an accurate distance to NGC 4151, which is currently not available. Recently reported distances range from 4 to 29 megaparsecs (Mpc). Strong peculiar motions make a redshift-based distance very uncertain, and the geometry of the galaxy and its nucleus prohibit accurate measurements using other techniques. Here we report a dust-parallax distance to NGC 4151 of $D_A = 19.0^{+2.4}_{-2.6}$ Mpc. The measurement is based on an adaptation of a geometric method proposed previously using the emission line regions of active galaxies. Since this region is too small for current imaging capabilities, we use instead the ratio of the physical-to-angular sizes of the more extended hot dust emission as determined from time-delays and infrared interferometry. This new distance leads to an approximately 1.4-fold increase in the dynamical black hole mass, implying a corresponding correction to emission line reverberation masses of black holes if they are calibrated against the two objects with additional dynamical masses.Comment: Authors' version of a letter published in Nature (27 November 2014); 8 pages, 5 figures, 1 tabl

Hydrography and circulation west of Sardinia in June 2014

In the frame of the REP14-MED sea trial in June 2014, the hydrography and circulation west of Sardinia, observed by means of gliders, shipborne CTD (conductivity, temperature, depth) instruments, towed devices, and vessel-mounted ADCPs (acoustic doppler current profilers), are presented and compared with previous knowledge. So far, the circulation is not well-known in this area, and the hydrography is subject to long-term changes. Potential temperature, salinity, and potential density ranges as well as core values of the observed water masses were determined. Modified Atlantic Water (MAW), with potential density anomalies below 28.72 kg m−3, showed a salinity minimum of 37.93 at 50 dbar. Levantine Intermediate Water (LIW), with a salinity maximum of about 38.70 at 400 dbar, was observed within a range of 28.72<σΘ/(kg m−3) < 29.10. MAW and LIW showed slightly higher salinities than previous investigations. During the trial, LIW covered the whole area from the Sardinian shelf to 7°15′ E. Only north of 40° N was it tied to the continental slope. Within the MAW, a cold and saline anticyclonic eddy was observed in the southern trial area. The strongest variability in temperature and salinity appeared around this eddy, and in the southwestern part of the domain, where unusually low saline surface water entered the area towards the end of the experiment. An anticyclonic eddy of Winter Intermediate Water was recorded moving northward at 0.014 m s−1. Geostrophic currents and water mass transports calculated across zonal and meridional transects showed a good agreement with vessel-mounted ADCP measurements. Within the MAW, northward currents were observed over the shelf and offshore, while a southward transport of about 1.5 Sv occurred over the slope. A net northward transport of 0.38 Sv across the southern transect decreased to zero in the north. Within the LIW, northward transports of 0.6 Sv across the southern transects were mainly observed offshore, and decreased to 0.3 Sv in the north where they were primarily located over the slope. This presentation of the REP14-MED observations helps to further understand the long-term evolution of hydrography and circulation in the Western Mediterranean, where considerable changes occurred after the Eastern Mediterranean Transient and the Western Mediterranean Transition

Steps Toward Determination of the Size and Structure of the Broad-Line Region in Active Galactic Nuclei. XVI. A Thirteen-Year Study of Spectral Variability in NGC 5548

We present the final installment of an intensive 13-year study of variations of the optical continuum and broad H-beta emission line in the Seyfert 1 galaxy NGC 5548. The data base consists of 1530 optical continuum measurements and 1248 H-beta measurements. The H-beta variations follow the continuum variations closely, with a typical time delay of about 20 days. However, a year-by-year analysis shows that the magnitude of emission-line time delay is correlated with the mean continuum flux. We argue that the data are consistent with the simple model prediction that the size of the broad-line region is proportional to the square root of the ionizing luminosity. Moreover, the apparently linear nature of the correlation between the H-beta response time and the nonstellar optical continuum arises as a consequence of the changing shape of the continuum as it varies, specifically with the optical (5100 A) continuum luminosity proportional to the ultraviolet (1350 A) continuum luminosity to the 0.56 power.Comment: 20 pages plus 4 figures. Accepted for publication in The Astrophysical Journa

Parameter identification problems in the modelling of cell motility

We present a novel parameter identification algorithm for the estimation of parameters in models of cell motility using imaging data of migrating cells. Two alternative formulations of the objective functional that measures the difference between the computed and observed data are proposed and the parameter identification problem is formulated as a minimisation problem of nonlinear least squares type. A Levenberg–Marquardt based optimisation method is applied to the solution of the minimisation problem and the details of the implementation are discussed. A number of numerical experiments are presented which illustrate the robustness of the algorithm to parameter identification in the presence of large deformations and noisy data and parameter identification in three dimensional models of cell motility. An application to experimental data is also presented in which we seek to identify parameters in a model for the monopolar growth of fission yeast cells using experimental imaging data. Our numerical tests allow us to compare the method with the two different formulations of the objective functional and we conclude that the results with both objective functionals seem to agree

The radio luminosity, black hole mass and Eddington ratio for quasars from the Sloan Digital Sky Survey

We investigate the \mbh- \sigma_* relation for radio-loud quasars with redshift $z<0.83$ in Data Release 3 of the Sloan Digital Sky Survey (SDSS). The sample consists of 3772 quasars with better model of H$\beta$ and \oiii lines and available radio luminosity, including 306 radio-loud quasars, 3466 radio-quiet quasars with measured radio luminosity or upper-limit of radio luminosity (181 radio-quiet quasars with measured radio luminosity). The virial supermassive black hole mass (\mbh) is calculated from the broad \hb line, the host stellar velocity dispersion ($\sigma_*$) is traced by the core \oiii gaseous velocity dispersion, and the radio luminosity and the radio loudness are derived from the FIRST catalog. Our results are follows: (1) For radio-quiet quasars, we confirm that there is no obvious deviation from the \mbh- \sigma_* relation defined in inactive galaxies when \mbh uncertainties and luminosity bias are concerned. (2) We find that radio-loud quasars deviate much from the \mbh- \sigma_* relation respect to that for radio-quiet quasars. This deviation is only partly due to the possible cosmology evolution of the \mbh- \sigma_* relation and the luminosity bias. (3) The radio luminosity is proportional to \mbh^{1.28^{+0.23}_{-0.16}}(\lb/\ledd)^{1.29^{+0.31}_{-0.24}} for radio-quiet quasars and \mbh^{3.10^{+0.60}_{-0.70}}(\lb/\ledd)^{4.18^{+1.40}_{-1.10}} for radio-loud quasars. The weaker correlation of the radio luminosity dependence upon the mass and the Eddington ratio for radio-loud quasars shows that other physical effects would account for their radio luminosities, such as the black hole spin.Comment: 15 pages, 8 figures, 2 tables, accepted for publication in ChJA

Resolving the dynamical mass of a z~1.3 QSO host galaxy using SINFONI and Laser Guide Star assisted Adaptive Optics

Recent studies of the tight scaling relations between the masses of supermassive black holes and their host galaxies have suggested that in the past black holes constituted a larger fraction of their host galaxies' mass. However, these arguments are limited by selection effects and difficulties in determining robust host galaxy masses at high redshifts. Here we report the first results of a new, complementary diagnostic route: we directly determine a dynamical host galaxy mass for the z=1.3 luminous quasar J090543.56+043347.3 through high-spatial-resolution (0.47", 4kpc FWHM) observations of the host galaxy gas kinematics over 30x40 kpc using ESO/VLT/SINFONI with LGS/AO. Combining our result of M_dyn = 2.05+1.68_0.74 x 10^11 M_sun (within a radius 5.25 +- 1.05 kpc) with M_BH,MgII = 9.02 \pm 1.43 x 10^8 M_sun, M_BH,Halpha = 2.83 +1.93-1.13 x 10^8 M_sun, we find that the ratio of black hole mass to host galaxy dynamical mass for J090543.56+043347.3 matches the present-day relation for M_BH vs. M_Bulge,Dyn, well within the IR scatter, deviating at most a factor of two from the mean. J090543.56+043347.3 displays clear signs of an ongoing tidal interaction and of spatially extended star formation at a rate of 50-100 M_sun/yr, above the cosmic average for a galaxy of this mass and redshift. We argue that its subsequent evolution may move J090543.56+043347.3 even closer to the z=0 relation for M_BH vs. M_Bulge,Dyn. Our results support the picture where any substantive evolution in these relations must occur prior to z~1.3. Having demonstrated the power of this modelling approach we are currently analyzing similar data on seven further objects to better constrain such evolution.Comment: Accepted for publication in ApJ, 14 pages, 10 Figure